Adverse Events Common With rhBMP-2 Device

Action Points

Explain that in contrast to published reports from manufacturer-sponsored studies, a new analysis of FDA documents and other data sources suggests that up to half of patients receiving the Infuse spinal fusion device may experience adverse events related to the drug.

Note that the nature as well as the likelihood of adverse events varied considerably depending on the surgical approach -- cervical versus lumbar and posterior or posterolateral versus anterior.

In stark contrast to published reports from manufacturer-sponsored studies of the Infuse spinal fusion device that incorporates a biologic bone-building drug, a new analysis of FDA documents and other data sources suggests that up to half of patients receiving the device may experience adverse events related to the drug, researchers said.

The Infuse device, which delivers recombinant human bone morphogenetic protein-2 (rhBMP-2) to speed vertebral fusion in patients with chronic back pain, has adverse event rates of 10% to 50% depending on the approach, according to Eugene Carragee, MD, of Stanford University's outpatient clinic in Redwood City, Calif., and colleagues.

"This risk of adverse events associated with rhBMP-2 is 10 to 50 times the original estimates reported in the industry-sponsored peer-reviewed publications," Carragee and colleagues wrote online in The Spine Journal, which Carragee serves as editor-in-chief.

The investigators in each of 13 reports of studies funded by product manufacturer Medtronic and published from 2000 to 2009 claimed to find no adverse events attributable to rhBMP-2.

Their new analysis covers a broader range of adverse events in patients treated across the country. They found that the nature as well as the likelihood of adverse events varied considerably depending on the surgical approach -- cervical versus lumbar and posterior or posterolateral versus anterior.

Carragee and colleagues drew on FDA records of data from the Medtronic-sponsored studies as well as follow-up publications and administrative and organizational databases.

They found major discrepancies between the original published reports and the picture painted by the FDA and other data.

For example, in posterolateral lumbar fusion procedures, use of rhBMP-2 was associated with greater leg pain and poorer functional outcomes in the first weeks after surgery relative to the control patients -- a finding Carragee and colleagues called paradoxical, since morbidity associated with the bone grafting would have been greatest at that time.

Other adverse events that appeared common with Infuse included implant displacement, subsidence, infection, ectopic bone formation, and osteolysis.

Carragee and colleagues (who included his deputy editors for evidence and methods at the Spine Journal) indicated that the company-sponsored studies had designs that biased the results against the conventional surgery.

They cited protocols that did not require facet preparation and only allowed relatively small quantities of iliac crest bone to be used in the control procedure's graft, while also disallowing any grafts of local bone.

"These methodological choices would be expected to result in an increased risk of poorer quality fusion, nonunion, and potential clinical failure when compared with usual recommended practice," Carragee and colleagues declared.

They also noted that the designs required radiographic evidence of "bilateral, continuous trabeculated bone connecting the transverse processes" for an outcome of solid fusion to be recorded, which they argued would also selectively weigh against conventional fusion surgery.

But the apparent under-reporting of adverse events in the 13 original reports was most troublesome, Carragee and colleagues suggested.

"In the larger trials, there is evidence in each trial that rhBMP-2 complications may be common and may be serious; but in each publication these were unreported," they wrote.

The analysis also mentioned the financial ties between Medtronic and the investigators on the original 13 study reports. Published payment data indicated that some authors had associations valued at more than $10 million.

Carragee and another group of colleagues also wrote an editorial accompanying the analysis, in which they expanded on the potential for researchers' financial interests to influence their scientific interpretations and judgment.

They also lamented the inadequacies of journals' disclosure policies.

Carragee and colleagues pointed to the disclosure in one of the 13 reports on Infuse, appearing in Spine, which stated, "'The manuscript submitted does not contain information about medical device(s)/drug(s). Institutional funds were received in support of this work. No benefits in any form have been or will be received from a commercial party related directly or indirectly to the subject of this manuscript."

Said the editorialists, "Even the most cursory review shows that this was all about devices and drugs used in an off-label manner and reported by authors who, by conservative estimates, have tens of millions of dollars of financial association with the sponsor."

Carragee and colleagues promised that the Spine Journal would soon be making "editorial-, procedural- and disclosure-related changes" in its policies.

Carragee and colleagues declared that no external funding was received for the analysis or the editorial.

Carragee reported stock ownership in Intrinsic Spine, Cytonics, and Simpirica, and consulting relationships with Kaiser Permanente, the U.S. Department of Justice, and the Defense Department, as well as serving as editor-in-chief of The Spine Journal. Other authors of the data analysis indicated they had no relevant financial relationships.

Two co-authors of the editorial reported relationships with Intrinsic Therapeutics, and one had a relationship with Informa Healthcare.